Synthesis of cyclohexane derivatives useful as sensates in consumer products

ABSTRACT

The present invention provides synthetic routes for preparing various isomers of cyclohexane-based coolants, such as menthyl esters and menthanecarboxamide derivatives, in particular those substituted at the amide nitrogen, for example with an aromatic ring or aryl moiety. Such structures have high cooling potency and long lasting sensory effect, which make them useful in a wide variety of consumer products. One synthetic route involves a copper catalyzed coupling of a primary menthanecarboxamide with an aryl halide, such reaction working best in the presence of potassium phosphate and water. Using this synthetic route, specific isomers can be prepared including the menthanecarboxamide isomer having the same configuration as l-menthol and new isomers such as a neoisomer having opposite stereochemistry at the carboxamide (C-1) position. The neoisomer unexpectedly has potent and long lasting cooling effect. Preparation schemes for neoisomers of other menthyl derivatives which are useful as coolants, including esters, ethers, carboxy esters and other N-substituted carboxamides are also provided.

TECHNICAL FIELD

The present invention relates to preparation of cyclohexane-basedderivatives useful as sensates for consumer products such as oral careand skin care compositions. In one aspect, synthesis pathways aredeveloped for preparing various isomers of cyclohexane-based coolants,such as menthyl esters, menthyl ethers and menthanecarboxamidederivatives, in particular those substituted at the amide nitrogen.

BACKGROUND OF THE INVENTION

Coolants or compounds that have a physiological cooling effectparticularly on oral and other mucosal surfaces and skin are commoningredients in a wide variety of consumer products including ediblecompositions and personal and health care compositions and in flavor orperfume compositions for use in such products. Examples of ediblecompositions include confectionery, candies, chocolate, chewing gum,beverages and oral medicines. Personal care compositions for applicationto the skin, hair and mucosal surfaces include lotions or creams, skincleansers, shampoos and conditioners, wipes and towelettes and cosmeticproducts such as lipsticks and foundations. A particular class ofpersonal and health care compositions to which the present inventionrelates is for oral and throat care, which include products in powder,paste or liquid forms and which on being used are retained for a timesufficient to contact the surface and the internal mucous membrane ofthe oral or nasal cavities or the pharynx. Such products include forexample, mouthwashes, dental and throat lozenges, gargles, chewing gum,dentifrice or toothpastes, toothpicks, dental tablets and powders andtopical solutions for application in dental treatment, as well ascough-syrups, chewable antacids and digestion promoting preparations.

The pleasant cooling sensation provided by coolants contributes to theappeal and acceptability of the products. In particular, oral careproducts such as dentifrices and mouthwashes are formulated withcoolants because they provide breath freshening effects and a clean,cool, fresh feeling in the mouth.

A large number of coolant compounds of natural or synthetic origin havebeen described. The most well-known compound is menthol, particularlyl-menthol, which is found naturally in peppermint oil, notably of Menthaarvensis L and Mentha viridis L. Of the isomers of menthol, the l-isomeroccurs most widely in nature and is typically what is referred by thename menthol having coolant properties. L-menthol has the characteristicpeppermint odor, has a clean fresh taste and exerts a cooling sensationwhen applied to the skin and mucosal surfaces. Other isomers of menthol(neomenthol, isomenthol and neoisomenthol) have somewhat similar, butnot identical odor and taste, i.e., having disagreeable notes describedas earthy, camphor, musty. The biggest difference among the isomers isin their cooling potency. L-menthol provides the most potent cooling,i.e., having the lowest cooling threshold of about 800 ppb, i.e., theconcentration where the cooling effect could be clearly recognized. Atthis level, there is no cooling effect for the other isomers. Forexample, d-neomenthol is reported to have a cooling threshold of about25,000 ppb and l-neomenthol about 3,000 ppb. [R. Emberger and R. Hopp,“Synthesis and Sensory Characterization of Menthol Enantiomers and TheirDerivatives for the Use in Nature Identical Peppermint Oils,” SpecialtyChemicals (1987), 7(3), 193-201]. This study demonstrated theoutstanding sensory properties of l-menthol in terms or cooling andfreshness and the influence of stereochemistry on the activity of thesemolecules.

Among synthetic coolants, many are derivatives of or are structurallyrelated to menthol, i.e., containing the cyclohexane moiety, andderivatized with functional groups including carboxamide, ketal, ester,ether and alcohol. Examples include the ρ-menthanecarboxamide compoundssuch as N-ethyl-ρ-menthan-3-carboxamide, known commercially as “WS-3”,and others in the series such as WS-5(N-ethoxycarbonylmethyl-ρ-menthan-3-carboxamide), WS-12[N-(4-methoxyphenyl)-ρ-menthan-3-carboxamide] and WS-14(N-tert-butyl-ρ-menthan-3-carboxamide). Examples of menthane carboxyesters include WS-4 and WS-30. An example of a synthetic carboxamidecoolant that is structurally unrelated to menthol isN,2,3-trimethyl-2-isopropylbutanamide, known as “WS-23”. Additionalexamples of synthetic coolants include alcohol derivatives such as3-(1-menthoxy)-propane-1,2-diol known as TK-10, isopulegol (under thetradename Coolact P) and ρ-menthane-3,8-diol (under the tradenameCoolact 38D) all available from Takasago; menthone glycerol acetal knownas MGA; menthyl esters such as menthyl acetate, menthyl acetoacetate,menthyl lactate known as Frescolat® supplied by Haarmann and Reimer, andmonomenthyl succinate under the tradename Physcool from V. Mane. TK-10is described in U.S. Pat. No. 4,459,425 to Amano et al. Other alcoholand ether derivatives of menthol are described e.g., in GB 1,315,626 andin U.S. Pat. Nos. 4,029,759; 5,608,119; and 6,956,139. WS-3 and othercarboxamide cooling agents are described for example in U.S. Pat. Nos.4,136,163; 4,150,052; 4,153,679; 4,157,384; 4,178,459 and 4,230,688.Additional N-substituted ρ-menthane carboxamides include amino acidderivatives such as those disclosed in WO 2006/103401 and in U.S. Pat.Nos. 4,136,163; 4,178,459 and 7,189,760 such asN-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)glycine ethyl esterand N-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)alanine ethylester. Menthyl esters including those of amino acids such as glycine andalanine are disclosed e.g., in EP 310,299 and in U.S. Pat. Nos.3,111,127; 3,917,613; 3,991,178; 5,5703,123; 5,725,865; 5,843,466;6,365,215; 6,451,844; and 6,884,903. Ketal derivatives are described,e.g., in U.S. Pat. Nos. 5,266,592; 5,977,166 and 5,451,404. Additionalagents that are structurally unrelated to menthol but have been reportedto have a similar physiological cooling effect include alpha-ketoenamine derivatives described in U.S. Pat. No. 6,592,884 including3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (3-MPC),5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (5-MPC), and2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone (DMPF); icilin (alsoknown as AG-3-5, chemical name1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one)described in Wei et al., J. Pharm. Pharmacol. (1983), 35:110-112.Reviews on the coolant activity of menthol and synthetic coolantsinclude H. R. Watson, et al. J. Soc. Cosmet. Chem. (1978), 29, 185-200and R. Eccles, J. Pharm. Pharmacol., (1994), 46, 618-630.

Many of the compounds above including menthol have relatively lowpotency and the duration of the cooling effect is typically short-lived.Thus, it is necessary to include fairly high levels of such compoundswhen formulating products, which increases cost. In addition, many ofthese compounds are relatively high cost ingredients since they areexpensive to manufacture on an industrial scale. Therefore, compoundswith high cooling potency and long lasting sensory effect are highlysought that will require only small amounts for incorporation in avariety of consumer products to provide high impact and long-lastingeffect. Such potent and long lasting coolant compounds have recentlybeen described for example in WO 2005/049553A1 to Givaudan includingρ-menthane carboxamides substituted at the N-position with an arylmoiety bearing certain substituents. Examples includeN-(4-cyanomethylphenyl)-ρ-menthanecarboxamide;N-(4-sulfamoylphenyl)-ρ-menthanecarboxamide;N-(4-cyanophenyl)-ρ-menthanecarboxamide;N-(4-acetylphenyl)-ρ-menthanecarboxamide,N-(4-hydroxymethylphenyl)-ρ-menthanecarboxamide andN-(3-hydroxy-4-methoxyphenyl)-ρ-menthanecarboxamide. In particular, anisomer having the same configuration as l-menthol, i.e.,N-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide,has been commercialized by Givaudan under the trade name Evercool 180(also referred to as G-180), supplied as a solution in a flavor oil suchas spearmint or peppermint [Chemical & Engineering News (2007), 85(39),pp. 95-98]. This material has been demonstrated to provide intense andlong-lasting cooling effect and useful for incorporation in personalcare products such as dentifrice and mouthwash as described in commonlyassigned U.S. Application No. 61/003,863, filed Nov. 20, 2007.

Similar to other commercially available synthetic coolants, the newGivaudan Evercool (G-180) coolant is a relatively expensive ingredient.It is believed that this is due to the high cost of producing, purifyingand solubilizing the material. Givaudan's proposed synthetic route forthe Evercool material as described in WO 2005/049553A1 involves reactinga menthane acid chloride with an aminobenzyl cyanide, the latterbelieved to be a relatively expensive raw material. Thus in one aspect,the present invention provides an alternate synthesis pathway forpreparing menthane carboxamide derivatives utilizing significantly lessexpensive raw materials while achieving good yield. Additionally,methods of purifying and solubilizing coolant compounds are providedwhich facilitate incorporation of the coolants into a wide variety ofconsumer products.

SUMMARY OF THE INVENTION

The present invention provides synthetic routes for preparing variousisomers of cyclohexane-based coolants, such as menthyl esters andmenthanecarboxamide derivatives, in particular those substituted at theamide nitrogen, for example with an aromatic ring or aryl moiety. Suchstructures have high cooling potency and long lasting sensory effect,which make them useful in a wide variety of consumer products. Onesynthetic route involves a copper catalyzed coupling of a primarymenthanecarboxamide with an aryl halide, such reaction working best inthe presence of potassium phosphate and water. Using this syntheticroute, specific isomers can be prepared including thementhanecarboxamide isomer having the same configuration as l-mentholand new isomers such as a neoisomer having opposite stereochemistry atthe carboxamide (C-1) position. The neoisomer unexpectedly has potentand long lasting cooling effect. Neoisomers of other derivativesincluding menthyl esters, menthyl ethers, menthanecarboxy esters andother N-substituted menthanecarboxamides are also prepared anddemonstrated to be useful as coolants.

DETAILED DESCRIPTION OF THE INVENTION

While the specification concludes with claims particularly pointing outand distinctly claiming the invention, it is believed that the presentinvention will be better understood from the following description.

All percentages and ratios used hereinafter are by weight of totalcomposition, unless otherwise indicated. All percentages, ratios, andlevels of ingredients referred to herein are based on the actual amountof the ingredient, and do not include solvents, fillers, or othermaterials with which the ingredient may be combined as a commerciallyavailable product, unless otherwise indicated.

All measurements referred to herein are made at 25° C. unless otherwisespecified.

Herein, “comprising” means that other steps and other components whichdo not affect the end result can be added. This term encompasses theterms “consisting of” and “consisting essentially of.”

As used herein, the word “include,” and its variants, are intended to benon-limiting, such that recitation of items in a list is not to theexclusion of other like items that may also be useful in the materials,compositions, devices, and methods of this invention.

As used herein, the words “preferred”, “preferably” and variants referto embodiments of the invention that afford certain benefits, undercertain circumstances. However, other embodiments may also be preferred,under the same or other circumstances. Furthermore, the recitation ofone or more preferred embodiments does not imply that other embodimentsare not useful, and is not intended to exclude other embodiments fromthe scope of the invention.

By “oral care composition” is meant a product, which in the ordinarycourse of usage, is not intentionally swallowed for purposes of systemicadministration of particular therapeutic agents, but is rather retainedin the oral cavity for a time sufficient to contact substantially all ofthe dental surfaces and/or oral tissues for purposes of oral activity.The oral care composition may be in various forms including toothpaste,dentifrice, tooth gel, subgingival gel, mouthrinse, mousse, foam,mouthspray, lozenge, chewable tablet, chewing gum or denture product.The oral care composition may also be incorporated onto strips or filmsfor direct application or attachment to oral surfaces.

The term “dentifrice”, as used herein, includes paste, gel, or liquidformulations unless otherwise specified. The dentifrice composition maybe a single phase composition or may be a combination of two or moreseparate dentifrice compositions. The dentifrice composition may be inany desired form, such as deep striped, surface striped, multilayered,having a gel surrounding a paste, or any combination thereof. Eachdentifrice composition in a dentifrice comprising two or more separatedentifrice compositions may be contained in a physically separatedcompartment of a dispenser and dispensed side-by-side.

The term “dispenser”, as used herein, means any pump, tube, or containersuitable for dispensing compositions such as dentifrices.

The term “teeth”, as used herein, refers to natural teeth as well asartificial teeth or dental prosthesis.

The term “orally acceptable carrier or excipients” includes safe andeffective materials and conventional additives such as used in oral carecompositions including but not limited to fluoride ion sources,anti-calculus or anti-tartar agents, buffers, abrasives such as silica,alkali metal bicarbonate salts, thickening materials, humectants, water,surfactants, titanium dioxide, flavorants, sweetening agents, xylitol,coloring agents, and mixtures thereof.

Active and other ingredients useful herein may be categorized ordescribed herein by their cosmetic and/or therapeutic benefit or theirpostulated mode of action or function. However, it is to be understoodthat the active and other ingredients useful herein can, in someinstances, provide more than one cosmetic and/or therapeutic benefit orfunction or operate via more than one mode of action. Therefore,classifications herein are made for the sake of convenience and are notintended to limit an ingredient to the particularly stated function(s)or activities listed.

Herein, the terms “tartar” and “calculus” are used interchangeably andrefer to mineralized dental plaque biofilms.

In one aspect, the present invention provides a synthesis pathway forpreparing various isomers of cyclohexane-based carboxamide coolants,such as those substituted at the carboxamide N-position. Preferredsubstituents include an aryl moiety, such as a phenyl ring which mayalso bear particular substituents. One pathway involves a coppercatalyzed coupling of a primary carboxamide with an aryl halide such asillustrated below. In addition to the copper catalyst, a key driver tothis coupling reaction is the presence of potassium phosphate. Theaddition of water to the reaction medium produces consistent results.The copper catalyst may be provided for example by a copper halide suchas copper (I) iodide. This reaction is a modification of a relatedprocedure described in Journal of the American Chemical Society (2002),124(25), 7421-7428.

In the above structures R₁, R₂ and R₃ may be the same or different andmay each be hydrogen or one of R₁, R₂ and R₃ may be a group selectedfrom halogen, OH, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, NO₂, CN,cyano-C1-C4-alkyl, acetyl, SO₂NH₂, CHO, CO₂H and C1-C4 alkylcarboxylate; two of R₁, R₂ and R₃ may be H or C1-C4 alkyl. Preferably R₁is a group selected from CN, cyanomethyl, acetyl, SO₂NH₂, hydroxymethyland OCH₃ at the 4-position and both R₂ and R₃ are H.

Specifically, this chemistry can be applied to produce the coolantG-180, chemicallyN-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide,as follows:

In this reaction pathway, a menthane acid chloride (designated asWS-1-C1) is reacted with NH₃/H₂O to prepare the menthane carboxamide,which is then reacted with cyanomethylphenyl iodide to produce thedesired G-180 product. The coupling reaction has been found to work bestin the presence of potassium phosphate. The addition of water to thereaction medium produces consistent results. The reaction isstereospecific, maintaining the (1R,2S,5R)-configuration of the abovestarting menthanecarboxamide.

Rather than starting from a menthane acid chloride as shown above, apreferred means of obtaining the primary menthane carboxamide materialis via hydrolysis of the corresponding nitrile as illustrated below. Thementhane nitrile can be obtained from the related alcohol, for example,menthol. It has been found that the reaction of menthane tosylate withsodium cyanide produces a nitrile having opposite stereochemistry at the1-position from the starting alcohol to produce the menthane tosylate.For example, starting from l-menthol (having 1R,2S,5R configuration) the(1S,2S,5R)-menthane nitrile is produced, i.e., differing instereochemistry at the C-1 position [Tetrahedron: Asymmetry (1996),7(7), 1967072]. This stereochemistry is maintained through thehydrolysis of the (1S,2S,5R)-menthane nitrile to produce the menthanecarboxamide and through the subsequent coupling reaction of the menthanecarboxamide with the aryl iodide to produce the final product. Thepresent pathway can thus be used to prepare various isomers includingthe example below designated herein as a neoisomer, which was preparedstarting from l-menthol, a readily available and relatively inexpensiveraw material. The neoisomer, i.e.,N-[4-(cyanomethyl)phenyl]-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide,unexpectedly is found to have excellent cooling properties.

The aryl iodide used in the above examples may be prepared using thefollowing synthetic routes as described in WO 2004/013094 and in Journalof Medicinal Chemistry (2005), 48(5), 1336-1343.

The present chemistry may also be modified to prepare otherN-substituted menthanecarboxamide derivatives, including non-aromaticand aliphatic derivatives. For example, the derivative WS-3(N-ethyl-ρ-menthan-3-carboxamide) could be prepared by reacting thementhane carboxamide with ethyl iodide in the presence of potassiumtert-butoxide as base in diethyl ether containingdicyclohexyl-18-crown-6.

A key advantage of the present reaction scheme is its stereospecificitywhich enables the preparation of specific isomers or mixtures ofisomers. For example, the G-180 and neoisomer materials may beseparately prepared and the two isomers combined at a ratio ranging from1:99 to 99:1. Alternatively, the preparation of any desired mixture ofisomers may be conducted by starting with an appropriate proportion ofthe different starting material isomers. In particular, mixing the twoisomers is advantageous in modulating the negative sensory effects fromusing G-180 alone. In sensory evaluations, panelists have described thesensory effect of G-180 as including a “burning” sensation especiallywhen used at fairly high levels. Mixing the isomers results in animproved overall sensation.

The discovery of the neoisomers of N-aryl substituted menthanecarboxamides such as the neo-G-180 neoisomer and its unexpected coolantproperties and advantages led to the development of additional synthesisschemes for preparation of neoisomers of other N-substituted menthanecarboxamide compounds of the general formula

wherein R is selected from linear or branched C1-C8 alkyl, substitutedC1-C8 alkyl, substituted or unsubstituted aryl or heteroaryl. Thesubstituents on the alkyl chain, aryl ring or heteroaryl ring includethe same substituents on the phenyl ring derivatives described above,i.e., halogen, OH, hydroxy-C1-C4-alkyl, alkoxy, amino, aminoalkyl, NO₂,CN, cyano-C1-C4-alkyl, acetyl, SO₂NH₂, CHO, CO₂H and C1-C4 alkylcarboxylate.

The (1S,2S,5R)-menthane nitrile (neo-menthyl cyanide) used to obtain theprimary menthane carboxamide for the scheme described above, can also beconverted to neo-WS-1 via an alternative hydrolysis using e.g.,hydrobromic acid. The neo-WS-1 can be used as a precursor to theneoisomer analogs of other known coolants. For example, preparation ofneo-menthane carboxamides such as neo-WS-3 and neo-WS-5 and neo-menthanecarboxy esters such as neo-WS-4 and neo-WS-30 are shown below.

Another set of hydrolysis conditions (e.g., KOH in tert-butanol) can beused to convert the (1S,2S,5R)-menthane nitrile (neo-menthyl cyanide) toWS-1 with (1R,2S,5R) absolute stereochemistry. In this case the nitrilefunctionality is both hydrolyzed and the C-1 stereocenter is isomerized.This provides an alternate means of producing WS-1, a usefulintermediate for the production of many coolants. For example, WS-1 canbe converted to known coolants, such as WS-3 and WS-5. This can be doneby directly using WS-1 or via the acid chloride (WS-1-C1) or otheractivated derivatives as shown below. The corresponding amide can beproduced and used as described above as a precursor to N-substitutedmenthanecarboxamide derivatives.

Further, l-menthol (having the 1R,2S,5R configuration) can be used as aprecursor to neo-menthol (having the 1S,2S,5R configuration). Theneo-menthol can then be converted to a number of other neo-menthylanalogs including such as esters and ethers that can serve as coolantsas shown in the following examples. Neo-menthol can be reacted with aderivatizing agent such as a carboxylic acid, carboxylic acid anhydride,dicarboxylic acid anhydride or carboxylic acid chloride to obtainneo-menthyl esters.

In another example, neo-monomenthyl succinate is prepared using succinicanhydride to avoid making the diester with succinic acid.

One example of a neo-menthyl ether derivative that can be prepared fromneo-menthol is 3-(neo-menthoxy)-1,2-propanediol (neo-TK-10) usingschemes similar to those reported for preparation of the l-version ofthe TK-10 coolant in U.S. Pat. Nos. 4,459,425; 5,608,119; 6,407,293 and6,515,188 all assigned to Takasago. For example, the following scheme isused to prepare neo-TK-10.

The following chemical abbreviations are used in the above preparationschemes:

DMF = Dimethyl formamide DMAP = N,N-Dimethylaminopyridine DMSO =Dimethyl sulfoxide HOAc = Acetic acid NaOAc = Sodium acetate NBS =N-Bromosuccinimde TsCl = Tosyl chloride TsOH = ρ-Toluenesulfonic acid

The coolant properties of the materials prepared according to thepresent methods are evaluated using sensory studies. For example, thementhane carboxamides G-180 and neo-G180 materials were found to providea cooling sensation similar to that produced by menthol, but longerlasting at significantly lower concentrations. Menthol generallyprovides an initial high cooling impact, but its effect is somewhattransient in that the cooling sensation drops sharply within a fewminutes after use. By contrast, both the G-180 and neoisomer materialsprovided a sensation that lasted longer than about 15 minutes. Thecooling potency of the neoisomer is particularly unexpected, sincestereochemistry is a major factor influencing coolant activity andpotency for menthol and menthol derivatives as reported in previousstudies. [See for example, R. Emberger and R. Hopp (1987), SpecialtyChemicals, 7(3), 193-201; R. Eccles (1990), Chemical Senses, 2, 275-291;S. Rovner (2007), Chemical & Engineering News, 85(39), 95-98]. Accordingto the C&EN report, the Givaudan scientists found that the coolingactivity of isomers in which the configuration did not match those ofl-menthol, specifically at the C-1 position were considerably lesspotent and in some cases had no activity at all. The effect on activityof these isomers is far more significant than is observed with menthol.

As demonstrated in sensory studies, the neoisomer provided unexpectedcooling potency and long lasting sensation. Importantly the sensationprovided by the neoisomer had significantly less of the “burning”sensation that has been attributed to the G-180 coolant.

Sensory evaluation studies of coolant activity may be conducted using amethodology patterned after the techniques described in M. C. Meilgaard,et al., Sensory Evaluation Techniques, 4^(th) Ed. (2007). A panel oftrained sensory experts evaluates cooling sensation experienced afterusing a product with coolant, for example by brushing with a dentifriceor rinsing with an aqueous rinse. In one protocol, panelists brush teethwith 1.5 grams of a test dentifrice (containing coolant) or control (nocoolant) and then expectorate. After brush expectoration, panelistsevaluate cooling intensity, assigning a number between 0 (no cooling) to60 (intense cooling). In a rinse protocol, panelists rinse mouth with 15ml. of an aqueous rinse and expectorate. After rinse expectoration,panelists evaluate cooling intensity according to the same 0 to 60scale. Evaluations are conducted various time points, for example, at 5,15, 30, 45, 60 minute, etc. At each evaluation, panelists are instructedto breathe in through pursed lips and evaluate overall coolingsensation. In this test, a numerical score of 7.5 indicates meaningfulor definite cooling.

In one embodiment of the present invention, a neoisomer coolant alone ormixed with the corresponding l-isomer and optionally additionalcoolants, is incorporated in oral care compositions, typically as partof the flavor system. For example a mixture of G-180 and neo-G-180 areincluded in a flavor system. The flavor system and other components oringredients of oral care compositions are described in the followingparagraphs along with non-limiting examples. These ingredients includeactive agents and other orally acceptable carrier materials which aresuitable for topical oral administration. By “compatible” is meant thatthe components of the composition are capable of being commingledwithout interaction in a manner which would substantially reducecomposition stability and/or efficacy. Suitable active agents, carrieror excipient materials are well known in the art. Their selection willdepend on desired activity, product form and secondary considerationslike taste, cost, and shelf stability, etc.

Suitable carrier materials or components of toothpaste, tooth gel or thelike include abrasive materials, sudsing agents, binders, humectants,flavoring and sweetening agents, etc. as disclosed in e.g., U.S. Pat.No. 3,988,433, to Benedict. Carrier materials for biphasic dentifriceformulations are disclosed in U.S. Pat. Nos. 5,213,790; 5,145,666 and5,281,410 all to Lukacovic et al. and in U.S. Pat. Nos. 4,849,213 and4,528,180 to Schaeffer. Mouthwash, rinse or mouth spray carriermaterials typically include water, flavoring and sweetening agents,etc., as disclosed in, e.g., U.S. Pat. No. 3,988,433 to Benedict.Lozenge carrier materials typically include a candy base; chewing gumcarrier materials include a gum base, flavoring and sweetening agents,as in, e.g., U.S. Pat. No. 4,083,955, to Grabenstetter et al. Sachetcarrier materials typically include a sachet bag, flavoring andsweetening agents. For subgingival gels used for delivery of activesinto the periodontal pockets or around the periodontal pockets, a“subgingival gel carrier” is chosen as disclosed in, e.g. U.S. Pat. Nos.5,198,220 and 5,242,910 both to Damani.

In one embodiment, the compositions of the subject invention are in theform of dentifrices, such as toothpastes, tooth gels and tooth powders.Components of such toothpaste and tooth gels generally include one ormore of a dental abrasive (from about 6% to about 50%), a surfactant(from about 0.5% to about 10%), a thickening agent (from about 0.1% toabout 5%), a humectant (from about 10% to about 55%), a flavoring agent(from about 0.04% to about 2%), a sweetening agent (from about 0.1% toabout 3%), a coloring agent (from about 0.01% to about 0.5%) and water(from about 2% to about 45%). Such toothpaste or tooth gel may alsoinclude one or more of an anticaries agent (from about 0.05% to about0.3% as fluoride ion) and an anticalculus agent (from about 0.1% toabout 13%). Tooth powders, of course, contain substantially allnon-liquid components.

Other embodiments of the subject invention are liquid products,including mouthwashes or rinses, mouth sprays, dental solutions andirrigation fluids. Components of such mouthwashes and mouth spraystypically include one or more of water (from about 45% to about 95%),ethanol (from about 0% to about 25%), a humectant (from about 0% toabout 50%), a surfactant (from about 0.01% to about 7%), a flavoringagent (from about 0.04% to about 2%), a sweetening agent (from about0.1% to about 3%), and a coloring agent (from about 0.001% to about0.5%). Such mouthwashes and mouth sprays may also include one or more ofan anticaries agent (from about 0.05% to about 0.3% as fluoride ion) andan anticalculus agent (from about 0.1% to about 3%). Components ofdental solutions generally include one or more of water (from about 90%to about 99%), preservative (from about 0.01% to about 0.5%), thickeningagent (from 0% to about 5%), flavoring agent (from about 0.04% to about2%), sweetening agent (from about 0.1% to about 3%), and surfactant(from 0% to about 5%).

The compositions of the present invention may also be in the form ofnon-abrasive gels and subgingival gels, which may be aqueous ornon-aqueous. In still another aspect, the invention provides a dentalimplement impregnated with the present composition. The dental implementcomprises an implement for contact with teeth and other tissues in theoral cavity, said implement being impregnated with the presentcomposition. The dental implement can be impregnated fibers includingdental floss or tape, chips, strips, films and polymer fibers.

Flavor System

The neoisomer menthane coolants and optionally other coolants includingmenthol and synthetic coolants described above such as G-180, wouldtypically be part of a flavor system, preferably one that effectivelymasks any unpleasant taste and sensations due to certain components ofthe composition such as antimicrobial actives or peroxide. Pleasanttasting compositions improve user compliance to prescribed orrecommended use of oral care products. The present flavor system mayalso comprise traditional flavor components, in particular those thathave been found to be relatively stable in the presence of usual oralcare product carrier materials or excipients. The combination of theselected flavoring components with the coolant(s) provides a high-impactrefreshing sensation with a well-rounded flavor profile.

The oral care composition will comprise from about 0.001% to 1.5% byweight of the synthetic menthane coolant(s). Mixtures of the neoisomerand l-isomer of the menthane coolant, for example neo-G-180 and G-180,will range from about 1:99 to about 99:1. If present, typically thelevel of menthol in the final composition ranges from about 0.010% toabout 1.0%.

In addition to the coolant(s) above, the flavor system may compriseadditional flavor ingredients including but not limited to peppermintoil, corn mint oil, spearmint oil, oil of wintergreen, clove bud oil,cassia, sage, parsley oil, marjoram, lemon, lime, orange, cis-jasmone,2,5-dimethyl-4-hydroxy-3 (2H)-furanone,5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone, vanillin, ethyl vanillin,anisaldehyde, 3,4-methylenedioxybenzaldehyde, 3,4-dimethoxybenzaldehyde,4-hydroxybenzaldehyde, 2-methoxybenzaldehyde, benzaldehyde;cinnamaldehyde, hexyl cinnamaldehyde, alpha-methyl cinnamaldehyde,ortho-methoxy cinnamaldehyde, alpha-amyl cinnamaldehydepropenylguaethol, heliotropine, 4-cis-heptenal, diacetyl, methyl-ρ-tert-butylphenyl acetate, menthol, methyl salicylate, ethyl salicylate, 1-menthylacetate, oxanone, alpha-irisone, methyl cinnamate, ethyl cinnamate,butyl cinnamate, ethyl butyrate, ethyl acetate, methyl anthranilate,iso-amyl acetate, iso-amyl butyrate, allyl caproate, eugenol,eucalyptol, thymol, cinnamic alcohol, octanol, octanal, decanol,decanal, phenylethyl alcohol, benzyl alcohol, alpha-terpineol, linalool,limonene, citral, maltol, ethyl maltol, anethole, dihydroanethole,carvone, menthone, β-damascenone, ionone, gamma decalactone, gammanonalactone, gamma undecalactone and mixtures thereof. Generallysuitable flavoring ingredients are those containing structural featuresand functional groups that are less prone to redox reactions. Theseinclude derivatives of flavor chemicals that are saturated or containstable aromatic rings or ester groups. Also suitable are flavorchemicals that may undergo some oxidation or degradation withoutresulting in a significant change in the flavor character or profile.The flavor ingredients may be supplied in the composition as single orpurified chemicals or by addition of natural oils or extracts that havepreferably undergone a refining treatment to remove components that arerelatively unstable and may degrade and alter the desired flavorprofile, resulting in a less acceptable product from an organolepticstandpoint. Flavoring agents are generally used in the compositions atlevels of from about 0.001% to about 5%, by weight of the composition.

The flavor system will typically include a sweetening agent. Suitablesweeteners include those well known in the art, including both naturaland artificial sweeteners. Some suitable water-soluble sweetenersinclude monosaccharides, disaccharides and polysaccharides such asxylose, ribose, glucose (dextrose), mannose, galactose, fructose(levulose), sucrose (sugar), maltose, invert sugar (a mixture offructose and glucose derived from sucrose), partially hydrolyzed starch,corn syrup solids, dihydrochalcones, monellin, steviosides, andglycyrrhizin. Suitable water-soluble artificial sweeteners includesoluble saccharin salts, i.e., sodium or calcium saccharin salts,cyclamate salts, the sodium, ammonium or calcium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide, the potassiumsalt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide(acesulfame-K), the free acid form of saccharin, and the like. Othersuitable sweeteners include dipeptide based sweeteners, such asL-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalaninemethyl ester (aspartame) and materials described in U.S. Pat. No.3,492,131,L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate, methyl esters of L-aspartyl-L-phenylglycerin andL-aspartyl-L-2,5,dihydrophenyl-glycine,L-aspartyl-2,5-dihydro-L-phenylalanine,L-aspartyl-L-(1-cyclohexylen)-alanine, and the like. Water-solublesweeteners derived from naturally occurring water-soluble sweeteners,such as a chlorinated derivative of ordinary sugar (sucrose), known, forexample, under the product description of sucralose as well as proteinbased sweeteners such as thaumatoccous danielli (Thaumatin I and II) canbe used. A composition preferably contains from about 0.1% to about 10%of sweetener, preferably from about 0.1% to about 1%, by weight of thecomposition.

In addition the flavor system may include salivating agents, warmingagents, and numbing agents. These agents are present in the compositionsat a level of from about 0.001% to about 10%, preferably from about 0.1%to about 1%, by weight of the composition. Suitable salivating agentsinclude Jambu® manufactured by Takasago. Suitable numbing agents includebenzocaine, lidocaine, clove bud oil, and ethanol. Examples of warmingagents include ethanol, capsicum and nicotinate esters, such as benzylnicotinate. Use of agents with warming effects may of course alter thecooling effect of coolants and will need to be considered, particularlyin optimizing the level of coolants.

Calcium Ion Source

The present compositions may also include a calcium ion source. Asdescribed in commonly assigned US Application No. 61/003,863 calciumions provide enhanced activity of coolants in terms of onset, intensityor impact and duration. It has also been found that the potentiatingeffect of calcium ions on coolants, particularly the synthetic menthanecarboxamide derivatives is further enhanced in the presence of menthol.The source of calcium ions may be any physiologically acceptable calciumcompound including inorganic or organic salts such as halides (chloride,bromide, iodide, fluoride), nitrate, nitrite, phosphate, pyrophosphate,polyphosphate, sulfate, carbonate, hypochlorite, formate, acetate,citrate, lactate, maleate, gluconate, tartrate, glycerophosphate,butyrate, isobutyrate, oxalate, peptide, phosphopeptide or from oxidesor hydroxides. The calcium ion source may be water soluble,sparingly-soluble or insoluble and can provide a minimum level of atleast about 50 ppm calcium ions for potentiating activity. The level ofthe calcium ion source is of course also dependent on secondaryconsiderations such as aesthetics and stability of the compositions.Some calcium compounds may alter the overall taste of the composition,for example being described as “chalky” and would thus not be desirableat levels that produce such effects.

Fluoride Source

It is common to have a fluoride compound present in dentifrices andother oral compositions in an amount sufficient to give a fluoride ionconcentration in the composition of from about 0.0025% to about 5.0% byweight, preferably from about 0.005% to about 2.0% by weight to provideanticaries effectiveness. As discussed above, prevention of caries isessential for overall tooth health and integrity. A wide variety offluoride ion-yielding materials can be employed as sources of solublefluoride in the present compositions. Examples of suitable fluorideion-yielding materials are found in U.S. Pat. No. 3,535,421 to Briner etal. and U.S. Pat. No. 3,678,154 to Widder et al. Representative fluorideion sources include: stannous fluoride, sodium fluoride, potassiumfluoride, amine fluoride, sodium monofluorophosphate, indium fluorideand many others.

Antimicrobial Agent

The present compositions may include an antimicrobial agent, such as aquaternary ammonium antimicrobial agent to provide bactericidalefficacy, i.e., effectiveness in killing, and/or altering metabolism,and/or suppressing the growth of, microorganisms which causetopically-treatable infections and diseases of the oral cavity, such asplaque, caries, gingivitis, and periodontal disease. The antimicrobialquaternary ammonium compounds useful in the compositions of the presentinvention include those in which one or two of the substitutes on thequaternary nitrogen has a carbon chain length (typically alkyl group)from about 8 to about 20, typically from about 10 to about 18 carbonatoms while the remaining substitutes (typically alkyl or benzyl group)have a lower number of carbon atoms, such as from about 1 to about 7carbon atoms, typically methyl or ethyl groups. Dodecyl trimethylammonium bromide, tetradecylpyridinium chloride, domiphen bromide,N-tetradecyl-4-ethyl pyridinium chloride, dodecyl dimethyl(2-phenoxyethyl) ammonium bromide, benzyl dimethoylstearyl ammoniumchloride, cetylpyridinium chloride, quaternized5-amino-1,3-bis(2-ethyl-hexyl)-5-methyl hexahydropyrimidine,benzalkonium chloride, benzethonium chloride and methyl benzethoniumchloride are exemplary of typical quaternary ammonium antibacterialagents. Other compounds are bis[4-(R-amino)-1-pyridinium] alkanes asdisclosed in U.S. No. 4,206,215, Jun. 3, 1980 to Bailey. The pyridiniumcompounds are the preferred quaternary ammonium compounds, particularlypreferred being cetylpyridinium, or tetradecylpyridinium halide salts(i.e., chloride, bromide, fluoride and iodide). Most preferred iscetylpyridinium chloride. The quaternary ammonium antimicrobial agentsare included in the present invention at levels of at least about0.035%, preferably from about 0.045% to about 1.0%, more preferably fromabout 0.05% to about 0.10% by weight of the composition.

The present compositions may comprise a metal ion source that providesstannous ions, zinc ions, copper ions, or mixtures thereof asantimicrobial agent. The metal ion source can be a soluble or asparingly soluble compound of stannous, zinc, or copper with inorganicor organic counter ions. Examples include the fluoride, chloride,chlorofluoride, acetate, hexafluorozirconate, sulfate, tartrate,gluconate, citrate, malate, glycinate, pyrophosphate, metaphosphate,oxalate, phosphate, carbonate salts and oxides of stannous, zinc, andcopper.

Stannous, zinc and copper ions have been found to help in the reductionof gingivitis, plaque, sensitivity, and improved breath benefits. Aneffective amount is defined as from at least about 50 ppm to about20,000 ppm metal ion of the total composition, preferably from about 500ppm to about 15,000 ppm. More preferably, metal ions are present in anamount from about 3,000 ppm to about 13,000 ppm and even more preferablyfrom about 5,000 ppm to about 10,000 ppm. This is the total amount ofmetal ions (stannous, zinc, copper and mixtures thereof) for delivery tothe tooth surface.

Dentifrices containing stannous salts, particularly stannous fluorideand stannous chloride, are described in U.S. Pat. No. 5,004,597 toMajeti et al. Other descriptions of stannous salts are found in U.S.Pat. No. 5,578,293 issued to Prencipe et al. and in U.S. Pat. No.5,281,410 issued to Lukacovic et al. Other ingredients needed tostabilize the stannous may be included, such as the ingredientsdescribed in Majeti et al. and Prencipe et al.

The preferred stannous salts are stannous fluoride and stannous chloridedihydrate. Other suitable stannous salts include stannous acetate,stannous tartrate and sodium stannous citrate. Examples of suitable zincion sources are zinc oxide, zinc sulfate, zinc chloride, zinc citrate,zinc lactate, zinc gluconate, zinc malate, zinc tartrate, zinccarbonate, zinc phosphate, and other salts listed in U.S. Pat. No.4,022,880. Zinc citrate and zinc lactate are particularly preferred.Examples of suitable copper ion sources are listed in U.S. Pat. No.5,534,243. The combined metal ion source(s) will be present in an amountof from about 0.05% to about 11%, by weight of the final composition.Preferably, the metal ion sources are present in an amount of from about0.5 to about 7%, more preferably from about 1% to about 5%. Preferably,the stannous salts may be present in an amount of from about 0.1 toabout 7%, more preferably from about 1% to about 5%, and most preferablyfrom about 1.5% to about 3% by weight of the total composition. Theamount of zinc or copper salts used in the present invention ranges fromabout 0.01 to about 5%, preferably from about 0.05 to about 4%, morepreferably from about 0.1 to about 3.0%.

The present invention may also include other antimicrobial agentsincluding non-cationic antimicrobial agents such as halogenated diphenylethers, phenolic compounds including phenol and its homologs, mono andpoly-alkyl and aromatic halophenols, resorcinol and its derivatives,xylitol, bisphenolic compounds and halogenated salicylanilides, benzoicesters, and halogenated carbanilides. Also useful antimicrobials areenzymes, including endoglycosidase, papain, dextranase, mutanase, andmixtures thereof. Such agents are disclosed in U.S. Pat. No. 2,946,725,Jul. 26, 1960, to Norris et al. and in U.S. Pat. No. 4,051,234 to Gieskeet al. Examples of other antimicrobial agents include chlorhexidine,triclosan, triclosan monophosphate, and flavor oils such as thymol.Triclosan and other agents of this type are disclosed in Parran, Jr. etal., U.S. Pat. No. 5,015,466, and U.S. Pat. No. 4,894,220 to Nabi et al.These agents may be present at levels of from about 0.01% to about 1.5%,by weight of the dentifrice composition.

Anticalculus Agent

The present compositions may optionally include an anticalculus agent,such as a pyrophosphate salt as a source of pyrophosphate ion. Thepyrophosphate salts useful in the present compositions include themono-, di- and tetraalkali metal pyrophosphate salts and mixturesthereof. Disodium dihydrogen pyrophosphate (Na₂H₂P₂O₇), sodium acidpyrophosphate, tetrasodium pyrophosphate (Na₄P₂O₇), and tetrapotassiumpyrophosphate (K₄P₂O₇) in their unhydrated as well as hydrated forms arethe preferred species. In compositions of the present invention, thepyrophosphate salt may be present in one of three ways: predominatelydissolved, predominately undissolved, or a mixture of dissolved andundissolved pyrophosphate.

Compositions comprising predominately dissolved pyrophosphate refer tocompositions where at least one pyrophosphate ion source is in an amountsufficient to provide at least about 0.025% free pyrophosphate ions. Theamount of free pyrophosphate ions may be from about 1% to about 15%,from about 1.5% to about 10% in one embodiment, and from about 2% toabout 6% in another embodiment. Free pyrophosphate ions may be presentin a variety of protonated states depending on the pH of thecomposition.

Compositions comprising predominately undissolved pyrophosphate refer tocompositions containing no more than about 20% of the totalpyrophosphate salt dissolved in the composition, preferably less thanabout 10% of the total pyrophosphate dissolved in the composition.Tetrasodium pyrophosphate salt is a preferred pyrophosphate salt inthese compositions. Tetrasodium pyrophosphate may be the anhydrous saltform or the decahydrate form, or any other species stable in solid formin the dentifrice compositions. The salt is in its solid particle form,which may be its crystalline and/or amorphous state, with the particlesize of the salt preferably being small enough to be aestheticallyacceptable and readily soluble during use. The amount of pyrophosphatesalt useful in making these compositions is any tartar control effectiveamount, generally from about 1.5% to about 15%, preferably from about 2%to about 10%, and most preferably from about 3% to about 8%, by weightof the dentifrice composition.

Compositions may also comprise a mixture of dissolved and undissolvedpyrophosphate salts. Any of the above mentioned pyrophosphate salts maybe used.

The pyrophosphate salts are described in more detail in Kirk-OthmerEncyclopedia of Chemical Technology, Third Edition, Volume 17,Wiley-Interscience Publishers (1982).

Optional agents to be used in place of or in combination with thepyrophosphate salt include such known materials as longer chain (3 ormore) polyphosphates including tripolyphosphate, tetrapolyphosphate andhexametaphosphate; synthetic anionic polymers, including polyacrylatesand copolymers of maleic anhydride or acid and methyl vinyl ether (e.g.,Gantrez), as described, for example, in U.S. Pat. No. 4,627,977, toGaffar et al. as well as, e.g., polyamino propane sulfonic acid (AMPS),diphosphonates (e.g., EHDP; AHP), polypeptides (such as polyaspartic andpolyglutamic acids), and mixtures thereof.

Other Active Agents

Still another active agent that may be included in the presentcompositions is a tooth bleaching active selected from the groupconsisting of peroxides, perborates, percarbonates, peroxyacids,persulfates, and combinations thereof. Suitable peroxide compoundsinclude hydrogen peroxide, urea peroxide, calcium peroxide, sodiumperoxide, zinc peroxide and mixtures thereof. A preferred percarbonateis sodium percarbonate. Preferred persulfates are oxones.

Preferred peroxide sources for use in dentifrice formulations arecalcium peroxide and urea peroxide. Hydrogen peroxide and urea peroxideare preferred for use in mouthrinse formulations. The following amountsrepresent the amount of peroxide raw material, although the peroxidesource may contain ingredients other than the peroxide raw material. Thepresent composition may contain from about 0.01% to about 30%,preferably from about 0.1% to about 10%, and more preferably from about0.5% to about 5% of a peroxide source, by weight of the composition.

In addition to whitening, the peroxide also provides other benefits tothe oral cavity. It has long been recognized that hydrogen peroxide andother peroxygen-compounds are effective in curative and/or prophylactictreatments with respect to caries, dental plaque, gingivitis,periodontitis, mouth odor, recurrent aphthous ulcers, dentureirritations, orthodontic appliance lesions, postextraction andpostperiodontal surgery, traumatic oral lesions and mucosal infections,herpetic stomatitis and the like. Peroxide-containing agents in the oralcavity exert a chemomechanical action generating thousands of tinyoxygen bubbles produced by interaction with tissue and salivary enzymes.The swishing action of a mouthrinse enhances this inherentchemomechanical action. Such action has been recommended for delivery ofother agents into infected gingival crevices. Peroxide mouthrinses thusprevent colonization and multiplication of anaerobic bacteria known tobe associated with periodontal disease.

Another optional active agent that may be added to the presentcompositions is a dentinal desensitizing agent to controlhypersensitivity, such as salts of potassium, calcium, strontium and tinincluding nitrate, chloride, fluoride, phosphates, pyrophosphate,polyphosphate, citrate, oxalate and sulfate.

Tooth Substantive Agent

The present invention may include a tooth substantive agent such aspolymeric surface active agents (PMSA's), which are polyelectrolytes,more specifically anionic polymers. The PMSA's contain anionic groups,e.g., phosphate, phosphonate, carboxy, or mixtures thereof, and thus,have the capability to interact with cationic or positively chargedentities. The “mineral” descriptor is intended to convey that thesurface activity or substantivity of the polymer is toward mineralsurfaces such as calcium phosphate minerals in teeth.

Tooth substantive agents provide many benefits including providingprotection and resistance of teeth against erosion and wear derived frombinding of calcium minerals in teeth (hydroxyapatite) and/or depositionon the tooth surface of a protective surface coating. Dental erosion isa permanent loss of tooth substance from the surface due to the actionof chemicals, such as harsh abrasives and acids. The protective surfacecoating provides control of tooth surface characteristics includingmodification of surface hydrophilic and hydrophobic properties andresistance to acid attack. The tooth substantive agents may also providedesired surface conditioning effects including: 1) effective desorptionof portions of undesirable adsorbed pellicle proteins, in particularthose associated with tooth stain binding, calculus development andattraction of undesirable microbial species and 2) maintaining surfaceconditioning effects and control of pellicle film for extended periodsfollowing product use, including post brushing and throughout moreextended periods. The effect of modifying the surface hydrophilic andhydrophobic properties can be measured in terms of changes in watercontact angles, a relative decrease indicating a more hydrophilicsurface and a relative increase indicating a more hydrophobic surface.Many of the tooth substantive agents also provide tartar control orantistain/whitening or surface conditioning activities, hence providingmultiple clinical actions in improving overall health and structure ofteeth as well as appearance and tactile impression of teeth. It isbelieved the tooth substantive agents provide a stain prevention benefitbecause of their reactivity or substantivity to mineral surfaces,resulting in desorption of portions of undesirable adsorbed pellicleproteins, in particular those associated with binding color bodies thatstain teeth, calculus development and attraction of undesirablemicrobial species. The retention of these agents on teeth can alsoprevent stains from accruing due to disruption of binding sites of colorbodies on tooth surfaces.

Suitable examples of PMSA tooth substantive agents are polyelectrolytessuch as condensed phosphorylated polymers; polyphosphonates; copolymersof phosphate- or phosphonate-containing monomers or polymers with othermonomers such as ethylenically unsaturated monomers and amino acids orwith other polymers such as proteins, polypeptides, polysaccharides,poly(acrylate), poly(acrylamide), poly(methacrylate), poly(ethacrylate),poly(hydroxyalkylmethacrylate), poly(vinyl alcohol), poly(maleicanhydride), poly(maleate) poly(amide), poly(ethylene amine),poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) andpoly(vinyl benzyl chloride); polycarboxylates and carboxy-substitutedpolymers; and mixtures thereof. Suitable polymeric mineral surfaceactive agents include the carboxy-substituted alcohol polymers describedin U.S. Pat. Nos. 5,292,501; 5,213,789, 5,093,170; 5,009,882; and4,939,284; all to Degenhardt et al. and the diphosphonate-derivatizedpolymers in U.S. Pat. No. 5,011,913 to Benedict et al; the syntheticanionic polymers including polyacrylates and copolymers of maleicanhydride or acid and methyl vinyl ether (e.g., Gantrez), as described,for example, in U.S. Pat. No. 4,627,977, to Gaffar et al. A preferredpolymer is diphosphonate modified polyacrylic acid. Polymers withactivity must have sufficient surface binding propensity to desorbpellicle proteins and remain affixed to enamel surfaces. For toothsurfaces, polymers with end or side chain phosphate or phosphonatefunctions are preferred although other polymers with mineral bindingactivity may prove effective depending upon adsorption affinity.

Additional examples of suitable phosphonate containing polymeric mineralsurface active agents include the geminal diphosphonate polymersdisclosed as anticalculus agents in U.S. Pat. No. 4,877,603 toDegenhardt et al; phosphonate group containing copolymers disclosed inU.S. Pat. No. 4,749,758 to Dursch et al. and in GB 1,290,724 (bothassigned to Hoechst) suitable for use in detergent and cleaningcompositions; and the copolymers and cotelomers disclosed as useful forapplications including scale and corrosion inhibition, coatings, cementsand ion-exchange resins in U.S. Pat. No. 5,980,776 to Zakikhani et al.and U.S. Pat. No. 6,071,434 to Davis et al. Additional polymers includethe water-soluble copolymers of vinylphosphonic acid and acrylic acidand salts thereof disclosed in GB 1,290,724 wherein the copolymerscontain from about 10% to about 90% by weight vinylphosphonic acid andfrom about 90% to about 10% by weight acrylic acid, more particularlywherein the copolymers have a weight ratio of vinylphosphonic acid toacrylic acid of 70% vinylphosphonic acid to 30% acrylic acid; 50%vinylphosphonic acid to 50% acrylic acid; or 30% vinylphosphonic acid to70% acrylic acid. Other suitable polymers include the water solublepolymers disclosed by Zakikhani and Davis prepared by copolymerizingdiphosphonate or polyphosphonate monomers having one or more unsaturatedC═C bonds (e.g., vinylidene-1,1-diphosphonic acid and2-(hydroxyphosphinyl)ethylidene-1,1-diphosphonic acid), with at leastone further compound having unsaturated C═C bonds (e.g., acrylate andmethacrylate monomers). Suitable polymers include thediphosphonate/acrylate polymers supplied by Rhodia under the designationITC 1087 (Average MW 3000-60,000) and Polymer 1154 (Average MW6000-55,000).

A preferred PMSA is a polyphosphate. A polyphosphate is generallyunderstood to consist of two or more phosphate molecules arrangedprimarily in a linear configuration, although some cyclic derivativesmay be present. Although pyrophosphates (n=2) are technicallypolyphosphates, the polyphosphates desired are those having around threeor more phosphate groups so that surface adsorption at effectiveconcentrations produces sufficient non-bound phosphate functions, whichenhance the anionic surface charge as well as hydrophilic character ofthe surfaces. The inorganic polyphosphate salts desired includetripolyphosphate, tetrapolyphosphate and hexametaphosphate, amongothers. Polyphosphates larger than tetrapolyphosphate usually occur asamorphous glassy materials. Preferred in this invention are the linearpolyphosphates having the formula:

XO(XPO₃)_(n)X,

wherein X is sodium, potassium or ammonium and n averages from about 3to about 125. Preferred polyphosphates are those having n averaging fromabout 6 to about 21, such as those commercially known as Sodaphos (n≈6),Hexaphos (n≈13), and Glass H (n≈21) and manufactured by FMC Corporationand Astaris. These polyphosphates may be used alone or in combination.Polyphosphates are susceptible to hydrolysis in high water formulationsat acid pH, particularly below pH 5. Thus it is preferred to uselonger-chain polyphosphates, in particular Glass H with an average chainlength of about 21. It is believed such longer-chain polyphosphates whenundergoing hydrolysis produce shorter-chain polyphosphates which arestill effective to deposit onto teeth and provide a stain preventivebenefit. In addition to creating the surface modifying effects, thetooth substantive agent may also function to solubilize insoluble salts.For example, Glass H has been found to solubilize insoluble stannoussalts. Thus, in compositions containing stannous fluoride for example,Glass H contributes to decreasing the stain promoting effect ofstannous.

Other polyphosphorylated compounds may be used in addition to or insteadof the polyphosphate, in particular polyphosphorylated inositolcompounds such as phytic acid, myo-inositol pentakis(dihydrogenphosphate); myo-inositol tetrakis(dihydrogen phosphate), myo-inositoltrikis(dihydrogen phosphate), and an alkali metal, alkaline earth metalor ammonium salt thereof. Preferred herein is phytic acid, also known asmyo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate) or inositolhexaphosphoric acid, and its alkali metal, alkaline earth metal orammonium salts. Herein, the term “phytate” includes phytic acid and itssalts as well as the other polyphosphorylated inositol compounds.

Still other surface active organophosphate compounds useful as toothsubstantive agents include phosphate mono-, di- or triesters representedby the following general structure:

wherein Z¹, Z², or Z³ may be identical or different, at least one beingan organic moiety, preferably selected from linear or branched, alkyl oralkenyl group of from 6 to 22 carbon atoms, optionally substituted byone or more phosphate groups; alkoxylated alkyl or alkenyl,(poly)saccharide, polyol or polyether group.

Some preferred agents include alkyl or alkenyl phosphate estersrepresented by the following structure:

wherein R¹ represents a linear or branched, alkyl or alkenyl group offrom 6 to 22 carbon atoms, optionally substituted by one or morephosphate groups; n and m, are individually and separately, 2 to 4, anda and b, individually and separately, are 0 to 20; Z² and Z³ may beidentical or different, each represents hydrogen, alkali metal,ammonium, protonated alkyl amine or protonated functional alkyl aminesuch as an alkanolamine, or a R¹—(OC_(n)H_(2n))_(a)(OC_(m)H_(2m))_(b)—group. Examples of suitable agents include alkyl and alkyl (poly)alkoxyphosphates such as lauryl phosphate (tradenames MAP 230K and MAP 230Tfrom Croda); PPG5 ceteareth-10 phosphate (available from Croda under thetradename Crodaphos SG); Laureth-1 phosphate (tradenames MAP L210 fromRhodia, Phosten HLP-1 from Nikkol Chemical or Sunmaep L from Sunjin);Laureth-3 phosphate (tradenames MAP L130 from Rhodia or Foamphos L-3from Alzo or Emphiphos DF 1326 from Huntsman Chemical); Laureth-9phosphate (tradename Foamphos L-9 from Alzo); Trilaureth-4 phosphate(tradenames Hostaphat KL 340D from Clariant or TLP-4 from NikkolChemical); C12-18 PEG 9 phosphate (tradename Crafol AP261 from Cognis);Sodium dilaureth-10 phosphate (tradename DLP-10 from Nikkol Chemical).Particularly preferred agents are polymeric, for example thosecontaining repeating alkoxy groups as the polymeric portion, inparticular 3 or more ethoxy, propoxy isopropoxy or butoxy groups.

Additional suitable polymeric organophosphate agents include dextranphosphate, polyglucoside phosphate, alkyl polyglucoside phosphate,polyglyceryl phosphate, alkyl polyglyceryl phosphate, polyetherphosphates and alkoxylated polyol phosphates. Some specific examples arePEG phosphate, PPG phosphate, alkyl PPG phosphate, PEG/PPG phosphate,alkyl PEG/PPG phosphate, PEG/PPG/PEG phosphate, dipropylene glycolphosphate, PEG glyceryl phosphate, PBG (polybutylene glycol) phosphate,PEG cyclodextrin phosphate, PEG sorbitan phosphate, PEG alkyl sorbitanphosphate, and PEG methyl glucoside phosphate.

Suitable non-polymeric phosphates include alkyl mono glyceridephosphate, alkyl sorbitan phosphate, alkyl methyl glucoside phosphate,alkyl sucrose phosphates.

The amount of tooth substantive agent will typically be from about 0.1%to about 35% by weight of the total oral composition. In dentifriceformulations, the amount is preferably from about 2% to about 30%, morepreferably from about 5% to about 25%, and most preferably from about 6%to about 20%. In mouthrinse compositions, the amount of toothsubstantive agent is preferably from about 0.1% to 5% and morepreferably from about 0.5% to about 3%.

Chelating Agents

Another optional agent is a chelating agent, also called sequestrants,such as gluconic acid, tartaric acid, citric acid andpharmaceutically-acceptable salts thereof. Chelating agents are able tocomplex calcium found in the cell walls of the bacteria. Chelatingagents can also disrupt plaque by removing calcium from the calciumbridges which help hold this biomass intact. However, it is not desiredto use a chelating agent which has an affinity for calcium that is toohigh, as this may result in tooth demineralization, which is contrary tothe objects and intentions of the present invention. Suitable chelatingagents will generally have a calcium binding constant of about 10¹ to10⁵ to provide improved cleaning with reduced plaque and calculusformation. Chelating agents also have the ability to complex withmetallic ions and thus aid in preventing their adverse effects on thestability or appearance of products. Chelation of ions, such as iron orcopper, helps retard oxidative deterioration of finished products.

Examples of suitable chelating agents are sodium or potassium gluconateand citrate; citric acid/alkali metal citrate combination; disodiumtartrate; dipotassium tartrate; sodium potassium tartrate; sodiumhydrogen tartrate; potassium hydrogen tartrate; sodium, potassium orammonium polyphosphates and mixtures thereof. The chelating agent may beused from about 0.1% to about 2.5%, preferably from about 0.5% to about2.5% and more preferably from about 1.0% to about 2.5%.

Still other chelating agents suitable for use in the present inventionare the anionic polymeric polycarboxylates. Such materials are wellknown in the art, being employed in the form of their free acids orpartially or preferably fully neutralized water soluble alkali metal(e.g. potassium and preferably sodium) or ammonium salts. Examples are1:4 to 4:1 copolymers of maleic anhydride or acid with anotherpolymerizable ethylenically unsaturated monomer, preferably methyl vinylether (methoxyethylene) having a molecular weight (M.W.) of about 30,000to about 1,000,000. These copolymers are available for example asGantrez AN 139 (M.W. 500,000), AN 119 (M.W. 250,000) and S-97Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals Corporation.

Other operative polymeric polycarboxylates include the 1:1 copolymers ofmaleic anhydride with ethyl acrylate, hydroxyethyl methacrylate,N-vinyl-2-pyrrolidone, or ethylene, the latter being available forexample as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.Additional operative polymeric polycarboxylates are disclosed in U.S.Pat. No. 4,138,477 to Gaffar and U.S. Pat. No. 4,183,914 to Gaffar etal. and include copolymers of maleic anhydride with styrene, isobutyleneor ethyl vinyl ether; polyacrylic, polyitaconic and polymaleic acids;and sulfoacrylic oligomers of MW as low as 1,000 available as UniroyalND-2.

Surfactants

The present compositions will typically also comprise surfactants, alsocommonly referred to as sudsing agents. Suitable surfactants are thosewhich are reasonably stable and foam throughout a wide pH range. Thesurfactant may be anionic, nonionic, amphoteric, zwitterionic, cationic,or mixtures thereof. Preferred surfactants or surfactant mixtures arethose that are compatible with other components particularly actives andfunctional excipients whose activities may be compromised. For example,anionic surfactants, such as sodium alkyl sulfate and amphotericsurfactants, such as cocoamidopropyl betaine may be preferred for usewhen anionic agents such as polyphosphates and organophosphates areincluded in the compositions.

Anionic surfactants useful herein include the water-soluble salts ofalkyl sulfates having from 8 to 20 carbon atoms in the alkyl radical(e.g., sodium alkyl sulfate) and the water-soluble salts of sulfonatedmonoglycerides of fatty acids having from 8 to 20 carbon atoms. Sodiumlauryl sulfate (SLS) and sodium coconut monoglyceride sulfonates areexamples of anionic surfactants of this type. Other suitable anionicsurfactants are sarcosinates, such as sodium lauroyl sarcosinate,taurates, sodium lauryl sulfoacetate, sodium lauroyl isethionate, sodiumlaureth carboxylate, and sodium dodecyl benzenesulfonate. Mixtures ofanionic surfactants can also be employed. Many suitable anionicsurfactants are disclosed by Agricola et al., U.S. Pat. No. 3,959,458.The present composition typically comprises an anionic surfactant at alevel of from about 0.025% to about 9%, from about 0.05% to about 5% orfrom about 0.1% to about 1%.

Another suitable surfactant is one selected from the group consisting ofsarcosinate surfactants, isethionate surfactants and tauratesurfactants. Preferred for use herein are alkali metal or ammonium saltsof these surfactants, such as the sodium and potassium salts of thefollowing: lauroyl sarcosinate, myristoyl sarcosinate, palmitoylsarcosinate, stearoyl sarcosinate and oleoyl sarcosinate.

Zwitterionic or amphoteric surfactants useful in the present inventioninclude derivatives of aliphatic quaternary ammonium, phosphonium, andsulfonium compounds, in which the aliphatic radicals can be straightchain or branched, and wherein one of the aliphatic substituentscontains from about 8 to 18 carbon atoms and one contains an anionicwater-solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphateor phosphonate. Suitable betaine surfactants are disclosed in U.S. Pat.No. 5,180,577 to Polefka et al. Typical alkyl dimethyl betaines includedecyl betaine or 2-(N-decyl-N,N-dimethylammonio) acetate, coco betaineor 2-(N-coco-N,N-dimethyl ammonio) acetate, myristyl betaine, palmitylbetaine, lauryl betaine, cetyl betaine, cetyl betaine, stearyl betaine,etc. The amidobetaines are exemplified by cocoamidoethyl betaine,cocamidopropyl betaine (CAPB), and lauramidopropyl betaine.

Cationic surfactants useful in the present invention include derivativesof quaternary ammonium compounds having one long alkyl chain containingfrom about 8 to 18 carbon atoms such as lauryl trimethylammoniumchloride; cetyl pyridinium chloride; cetyl trimethylammonium bromide;coconut alkyltrimethylammonium nitrite; cetyl pyridinium fluoride; etc.Preferred compounds are the quaternary ammonium fluorides havingdetergent properties described in U.S. Pat. No. 3,535,421 to Briner etal. Certain cationic surfactants can also act as antimicrobials in thecompositions disclosed herein.

Useful nonionic surfactants include compounds produced by thecondensation of alkylene oxide groups (hydrophilic in nature) with anorganic hydrophobic compound which may be aliphatic or alkylaromatic innature. Examples of suitable nonionic surfactants include the Pluronics,polyethylene oxide condensates of alkyl phenols, products derived fromthe condensation of ethylene oxide with the reaction product ofpropylene oxide and ethylene diamine, ethylene oxide condensates ofaliphatic alcohols, long chain tertiary amine oxides, long chaintertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures ofsuch materials.

Abrasives

Dental abrasives useful in the compositions of the subject inventioninclude many different materials. The material selected must be onewhich is compatible within the composition of interest and does notexcessively abrade dentin. Suitable abrasives include, for example,silicas including gels and precipitates, insoluble sodiumpolymetaphosphate, hydrated alumina, calcium carbonate, dicalciumorthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate,calcium polymetaphosphate, and resinous abrasive materials such asparticulate condensation products of urea and formaldehyde.

Another class of abrasives for use in the present compositions is theparticulate thermo-setting polymerized resins as described in U.S. Pat.No. 3,070,510 issued to Cooley & Grabenstetter. Suitable resins include,for example, melamines, phenolics, ureas, melamine-ureas,melamine-formaldehydes, urea-formaldehyde, melamine-urea-formaldehydes,cross-linked epoxides, and cross-linked polyesters.

Silica dental abrasives of various types are preferred because of theirunique benefits of exceptional dental cleaning and polishing performancewithout unduly abrading tooth enamel or dentine. The silica abrasivepolishing materials herein, as well as other abrasives, generally havean average particle size ranging between about 0.1 to about 30 microns,and preferably from about 5 to about 15 microns. The abrasive can beprecipitated silica or silica gels such as the silica xerogels describedin Pader et al., U.S. Pat. No. 3,538,230 and DiGiulio, U.S. Pat. No.3,862,307. Examples include the silica xerogels marketed under the tradename “Syloid” by the W.R. Grace & Company, and precipitated silicamaterials such as those marketed by the J. M. Huber Corporation underthe trade name, Zeodent®, particularly the silicas carrying thedesignation Zeodent® 119, Zeodent® 118, Zeodent® 109 and Zeodent® 129.The types of silica dental abrasives useful in the toothpastes of thepresent invention are described in more detail in Wason, U.S. Pat. No.4,340,583; and in commonly-assigned U.S. Pat. Nos. 5,603,920; 5,589,160;5,658,553; 5,651,958; and 6,740,311. The silica abrasives describedtherein include various grades of silica such as standard or base silicaand high-cleaning or high-polishing silica.

Mixtures of abrasives can be used such as mixtures of the various gradesof Zeodent® silica abrasives listed above. The total amount of abrasivein dentifrice compositions of the subject invention typically range fromabout 6% to about 70% by weight; toothpastes preferably contain fromabout 10% to about 50% of abrasives. Dental solution, mouth spray,mouthwash and non-abrasive gel compositions of the subject inventiontypically contain little or no abrasive.

Miscellaneous Carrier Materials

Water employed in the preparation of commercially suitable oralcompositions should preferably be of low ion content and free of organicimpurities. Water may comprise up to about 99% by weight of the aqueouscompositions herein. These amounts of water include the free water whichis added plus that which is introduced with other materials, such aswith sorbitol.

The present invention may also include an alkali metal bicarbonate salt,which may serve a number of functions including abrasive, deodorant,buffering and adjusting pH. Alkali metal bicarbonate salts are solublein water and unless stabilized, tend to release carbon dioxide in anaqueous system. Sodium bicarbonate, also known as baking soda, is acommonly used bicarbonate salt. The present composition may contain fromabout 0.5% to about 30% by weight of an alkali metal bicarbonate salt.

The present compositions in the form of toothpastes, dentifrices andgels typically will contain some thickening material or binder toprovide a desirable consistency. Preferred thickening agents includecarboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, and watersoluble salts of cellulose ethers such as sodium carboxymethylcelluloseand sodium hydroxyethyl cellulose. Natural gums such as gum karaya,xanthan gum, gum arabic, and gum tragacanth can also be used. Colloidalmagnesium aluminum silicate or finely divided silica can be used as partof the thickening agent to further improve texture. Thickening agentsare typically used in an amount from about 0.1% to about 15%, by weight.

Another optional component of the present compositions is a humectant,which serves to keep toothpaste compositions from hardening uponexposure to air. Certain humectants can also impart desirable sweetnessof flavor to toothpaste compositions. Suitable humectants for use in theinvention include glycerin, sorbitol, polyethylene glycol, propyleneglycol, and other edible polyhydric alcohols. The humectant generallycomprises from about 0% to 70%, preferably from about 15% to 55%, byweight of the composition.

The pH of the present compositions may be adjusted through the use ofbuffering agents. Buffering agents, as used herein, refer to agents thatcan be used to adjust the pH of aqueous compositions such as mouthrinsesand dental solutions preferably to a range of about pH 4.0 to about pH8.0. Buffering agents include sodium bicarbonate, monosodium phosphate,trisodium phosphate, sodium hydroxide, sodium carbonate, sodium acidpyrophosphate, citric acid, and sodium citrate and are typicallyincluded at a level of from about 0.5% to about 10% by weight.

Poloxamers may be employed in the present compositions. A poloxamer isclassified as a nonionic surfactant and may also function as anemulsifying agent, binder, stabilizer, and other related functions.Poloxamers are difunctional block-polymers terminating in primaryhydroxyl groups with molecular weights ranging from 1,000 to above15,000. Poloxamers are sold under the tradename of Pluronics andPluraflo by BASF including Poloxamer 407 and Pluraflo L4370.

Other emulsifying agents that may be used include polymeric emulsifierssuch as the Pemulen® series available from B.F. Goodrich, and which arepredominantly high molecular weight polyacrylic acid polymers useful asemulsifiers for hydrophobic substances.

Titanium dioxide may also be added to the present compositions ascoloring or opacifying agent typically at a level of from about 0.25% toabout 5% by weight.

Other optional agents that may be used in the present compositionsinclude dimethicone copolyols selected from alkyl- andalkoxy-dimethicone copolyols, such as C12 to C20 alkyl dimethiconecopolyols and mixtures thereof, as aid in providing positive tooth feelbenefits. Highly preferred is cetyl dimethicone copolyol marketed underthe trade name Abil EM90. The dimethicone copolyol is generally presentfrom about 0.01% to about 25%, preferably from about 0.1% to about 5 byweight.

Method of Use

A method of use or treatment herein comprises contacting a subject'sdental enamel surfaces and mucosa in the mouth with the oralcompositions according to the present invention. The method may be bybrushing with a dentifrice or rinsing with a dentifrice slurry ormouthrinse. Other methods include contacting the topical oral gel,denture product, mouthspray, or other form with the subject's teeth andoral mucosa. The subject may be any person or animal whose oral cavityis contacted with the oral composition. By animal is meant to includehousehold pets or other domestic animals, or animals kept in captivity.

For example, a method of treatment may include brushing a dog's teethwith a dentifrice composition. Another example would include rinsing acat's mouth with an oral composition for a sufficient amount of time tosee a benefit. Pet care products such as chews and toys may beformulated to contain the present oral compositions. The composition maybe incorporated into a relatively supple but strong and durable materialsuch as rawhide, ropes made from natural or synthetic fibers, andpolymeric articles made from nylon, polyester or thermoplasticpolyurethane. As the animal chews, licks or gnaws the product, theincorporated active elements are released into the animal's oral cavityinto a salivary medium, comparable to an effective brushing or rinsing.

In one embodiment of the present invention, the method of use involves aregimen that comprises brushing with a dentifrice containing thecoolant(s) followed by rinsing with a rinse containing a potentiatingagent for the coolant(s). Or the dentifrice may contain the potentiatingagent and the rinse will contain the coolant(s). The regimen approach isadvantageous for example, when the potentiating agent such as a calciumion source may present stability problems with components of either thedentifrice or rinse or when there is a desire to delay the onset of theenhancing effect. In addition rinsing would ensure distribution ofcoolant and potentiating agent throughout the mouth resulting in a wholemouth feeling of refreshing cool sensation. In another embodiment, theregimen comprises brushing or rinsing with a product containing acalcium ion source, followed by chewing gum or sucking on a lozengecontaining coolant(s) to deliver long lasting cool sensation.Alternatively, the coolant(s) and potentiating agent may be present inall products used in the regimens.

EXAMPLES

The following examples further describe and demonstrate embodimentswithin the scope of the present invention. These examples are givensolely for the purpose of illustration and are not to be construed aslimitations of the present invention as many variations thereof arepossible without departing from the spirit and scope.

Example I Preparation ofN-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamideA. Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide

A 250 mL flask was purged with nitrogen, left under a nitrogenatmosphere, and charged with 13.0 g (0.0641 mol) of(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonyl chloride.

While stirring 130 mL of 29% ammonium hydroxide solution was added tothe flask. A white precipitate quickly formed, and after stirringovernight the fine white slurry was suction filtered. The filter cakewas washed with water (3×50 mL) then dried in a vacuum oven (RT, 5 mmHg, 3 days) to provide(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide as a white solidwith the following spectroscopic properties.

¹H NMR (500 MHz, CDCl₃): δ 0.78 (d, 3H), 0.88 (d, 3H), 0.91 (d, 3H),1.00 (m, 2H), 1.20 (m, 1H), 1.38 (m, 1H), 1.50 (m, 1H), 1.63-1.90 (m,4H), 2.08 (td, 1H), 5.45 (br s, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 16.26, 21.65, 22.57, 23.98, 28.84, 32.52,34.80, 39.73, 44.65, 49.30, 178.82.

MS (Ionspray): m/e 184 (MH⁺, 100%)

B. Coupling of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamidewith 4-(cyanomethyl)phenyl iodide

A 250 mL 3-neck flask was fitted with a condenser and a nitrogen inletwas charged with 10.00 g (0.0546 mol) of(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide, 0.522 g (0.0027mol) copper (I) iodide, 13.26 g (0.0546 mol) of 4-(cyanomethyl)phenyliodide, 23.18 g (0.109 mol) of potassium phosphate. The system waspurged with nitrogen and a magnetic stir bar was added. After theaddition of 170 mL of toluene, 3.42 g (0.190 mol) of water and 0.964 g(0.0109 mol) of N,N′-dimethylethylene diamine, the mixture was heated to100° C. and stirred for 21 h under nitrogen. The crude reaction mixturewas filtered through 50 g of silica gel (wet with 1:1 ethylacetate/methylene chloride), and the bed was rinsed three times with 1:1ethyl acetate/methylene chloride (150+75+75 mL). Concentration of themixture in vacuo providedN-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamideas a thick oil oil which was further purified by flash chromatography onsilica gel eluting with mixtures of ethyl acetate and hexanes. Theproduct has the following properties with the structure confirmed byobtaining an X-ray crystal structure of a sample crystallized fromhexane/ethyl acetate.

¹H NMR (500 MHz, CDCl₃): δ 0.82 (d, 3H), 0.89 (d, 3H), 0.93 (d, 3H),0.95-1.06 (m, 2H), 1.35 (m, 1H), 1.38 (m, 1H), 1.63 (t, 1H), 1.71-1.83(m, 3H), 1.91 (d, 1H), 2.20 (td, 1H), 3.72 (s, 2H), 7.23 (d, 2H), 7.51(br s, 1H), 7.56 (d, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 16.54, 21.64, 22.55, 23.33, 24.10, 29.09,32.52, 34.71, 39.63, 44.76, 50.90, 118.24, 120.68, 125.48, 128.74,138.22, 174.86.

MS (Ionspray): m/e 299 (MH⁺, 100%)

Mp: 146.0-149.5° C.

[α]^(27.5) _(D) −42.9° (0.0103 g/mL, CHCl₃)

Crystal Data and Structure Refinement:

Empirical formula C19 H26 N2 O

Formula weight 298.42

Temperature 571(2) K

Wavelength 1.54178 A

Crystal system Orthorhombic

Space group P2₁2₁2₁

Unit cell dimensions a=5.21430(10) A alpha=90 deg.

-   -   b=17.3974(5) A beta=90 deg.    -   c=19.4797(6) A gamma=90 deg.

Volume, Z 1767.11(8) Â3, 4

Density (calculated) 1.122 Mg/m̂3

Absorption coefficient 0.538 mm̂−1

F(000) 648

Crystal size 0.3×0.2×0.1 mm

Theta range for data collection 3.41 to 71.28 deg.

Limiting indices −6<=h<=5, −20<=k<=21, −23<=l<=23

Reflections collected 13300

Independent reflections 3316 [R(int)=0.0566]

Refinement method Full-matrix least-squares on F̂2

Data/restraints/parameters 3315/0/199

Goodness-of-fit on F̂2 1.040

Final R indices [I>2sigma(I)] R1=0.1001, wR2=0.2688

R indices (all data) R1=0.1288, wR2=0.3065

Absolute structure parameter 0.2(8)

Largest diff. peak and hole 0.854 and −0.424 e.Â−3

Example II Preparation of(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide andN-[4-(cyanomethyl)phenyl]-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamideA. Preparation of (1R,2S,5R)-menthyl tosylate

A solution of 50.10 g (0.321 mol) of (1R,2S,5R)-(−)-menthol in 300 mL ofpyridine in a 1 L Erlenmeyer flask was cooled to 0° C. in an ice bath,and 91.0 g (0.477 mol) of p-toluenesulfonyl chloride (TsCl) was addedwith stirring. The solution was kept in the ice bath between 0-10° C.for 2 h then sealed and stored in a 5° C. refrigerator for 23 h. Thereaction mixture was poured into 5 L of an ice/water mixture withstirring leading to a precipitate which was suction filtered after 30min. The white precipitate was rinsed on the funnel with 3×500 mL ofwater, then dried in a vacuum oven for 3 days (RT, 5 mm Hg) to providethe desired (1R,2S,5R)-menthyl tosylate for use in the preparation ofthe carbonitrile below (step B) having opposite stereochemistry at theC-1 position.

¹H NMR (500 MHz, CDCl₃): δ 0.55 (d, 3H), 0.82 (d, 3H), 0.90 (d, 3H),0.98 (m, 1H), 1.19 (m, 1H), 1.40 (m, 2H), 1.62 (m, 2H), 1.89 (m, 1H),2.16 (d, 1H), 2.43 (s, 3H), 4.40 (m, 1H), 7.34 (d, 2H), 7.80 (d, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 15.46, 21.09, 21.87, 22.11, 23.17, 25.70,31.90, 33.99, 42.19, 47.80, 83.92, 127.92, 129.91, 134.98, 144.56.

B. Preparation of (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile

To a solution of 6.33 g (20.4 mmol) of (1R,2S,5R)-menthyl tosylate in100 mL of dimethyl sulfoxide at room temperature was added 2.00 g (40.8mmol) of sodium cyanide. The mixture was heated to 90° C. under anitrogen atmosphere for 5 h. After cooling to room temperature themixture was diluted with 250 mL of water and extracted with 3×250 mL ofethyl acetate. The combined organic layers were extracted with 100 mL ofwater, dried over magnesium sulfate, and concentrated in vacuo toprovide (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile as alight yellow liquid.

¹H NMR (500 MHz, CDCl₃): δ 0.80-1.00 (m, 2H), 0.92 (d, 3H), 0.96 (d,6H), 1.11.17 (t, 1H), 1.29 (q, 1H), 1.60 (m, 1H), 1.75 (m, 1H), 1.80 (2,1H), 1.92 (d, 1H), 2.00 (d, 1H), 3.08 (br s, 1H).

¹³C NMR (125 MHz, CDCl₃): δ 20.82, 20.95, 22.01, 27.15, 28.70, 31.34,31.46, 34.72, 37.56, 45.82, 121.27.

C. Preparation of (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide

A solution of 0.105 g (0.634 mmol) of(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile in 4.9 mL ofdimethyl sulfoxide was placed in a 10 mL flask with a magnetic stir bar.After adding 0.60 mL of 35% hydrogen peroxide and 0.097 g (1.2 mmol) of50% sodium hydroxide solutions the flask was capped and stirred at roomtemperature for 20 h. The reaction mixture was diluted with 10 mL ofwater, extracted twice with 10 mL of methylene chloride. The combinedmethylene chloride layers were back extracted with 3×20 mL of water,dried over magnesium sulfate, and concentrated in vacuo to provide anoff-white solid that was further purified by column chromatography(silica gel, 75:25 hexane:ethyl acetate) to provide(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide.

¹H NMR (500 MHz, CDCl₃): δ 0.82 (d, 3H), 0.91 (d, 3H), 0.94 (d, 3H),0.94-1.05 (m, 2H), 1.19 (td, 1H), 1.68 (m, 2H), 1.75-1.90 (m, 4H), 2.66(br s, 1H), 5.50 (br s, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 21.65, 21.83, 22.73, 25.74, 27.40, 30.62,35.54, 39.50, 42.80, 46.74, 178.04.

MS (Ionspray): m/e 184 (MH⁺, 100%)

D. Preparation ofN-[4-(cyanomethyl)phenyl]-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide

N-[4-(cyanomethyl)phenyl]-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamidewas prepared as described above for the preparation of theN-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamideisomer, i.e., by coupling the(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide prepared in stepsA to C above with 4-(cyanomethyl)phenyl iodide. The (1S,2S,5R)-material(neoisomer) has the following properties with structure confirmed byobtaining an X-ray crystal structure of a sample crystallized fromhexane/ethyl acetate.

¹H NMR (500 MHz, CDCl₃): δ 0.80 (d, 3H), 0.90 (d, 3H), 0.93 (d, 3H),0.93-1.25 (m, 2H), 1.21 (m, 1H), 1.68 (m, 2H), 1.75-1.95 (m, 4H), 2.68(m, 1H), 5.50 (br s, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 21.65, 21.83, 22.73, 25.74, 27.40, 30.62,35.54, 39.50, 42.80, 46.74, 178.04.

MS (Ionspray): m/e 299 (MH⁺, 100%)

Mp: 167.0-169.0° C.

[α]^(27.5) _(D) +9.7° (0.0100 g/mL, CHCl₃)

Crystal Data and Structure Refinement:

Empirical formula C19 H26 N2 O

Formula weight 298.42

Temperature 571(2) K

Wavelength 1.54178 A

Crystal system Orthorhombic

Space group P2₁2₁2₁

Unit cell dimensions a=9.7487(3) A alpha=90 deg.

-   -   b=11.0154(3) A beta=90 deg.    -   c=16.0495(4) A gamma=90 deg.

Volume, Z 1723.49(8) Â3, 4

Density (calculated) 1.150 Mg/m̂3

Absorption coefficient 0.551 mm̂−1

F(000) 648

Crystal size 0.3×0.2×1 mm

Theta range for data collection 4.87 to 71.24 deg.

Limiting indices −11<=h<=9, −13<=k<=12, −19<=l<=19

Reflections collected 13352

Independent reflections 3242 [R(int)=0.0620]

Refinement method Full-matrix least-squares on F̂2

Data/restraints/parameters 3241/0/199

Goodness-of-fit on F̂2 1.004

Final R indices [I>2sigma(I)] R1=0.0441, wR2=0.0997

R indices (all data) R1=0.0682, wR2=0.1136

Absolute structure parameter −0.2(4)

Largest diff. peak and hole 0.118 and −0.150 e.Â−3

Example III Dentifrice Compositions

Dentifrice compositions (A-C) comprising the G-180 and neoisomercoolants made in Examples I and II respectively, were prepared usingconventional methods. Ingredients are shown in weight %. Results ofsensory evaluation of the compositions using a three-judge panel areshown below. Panelists brushed with each dentifrice and then rated thesensation after 10 minutes using a 5-point scale with 5 having thehighest intensity. The duration of the overall sensation which includedcooling as well as some peppery/irritation/burning in some cases wasrecorded up to when no more cooling/sensation occurred.

Dentifrice A B C Ingredients Wt. % Wt. % Wt. % Sorbitol 52.645 52.64552.645 Sodium Hydroxide 2.3 2.3 2.3 Silica 119 15.0 15.0 15.0 XanthanGum 0.7 0.7 0.7 Sodium Carboxymethylcellulose 0.2 0.2 0.2 Sodium AcidPyrophosphate 4.4 4.4 4.4 DI Water 10.0 10.0 10.0 Carbomer 956 0.4 0.40.4 Sodium Lauryl Sulfate (28% Solution) 5.0 5.0 5.0 Sodium Saccharin0.54 0.54 0.54 G-180 (Example I) 0.015 — 0.0075 Neo-G-180 (Example II) —0.015 0.0075 Rectified Peppermint Oil 1.0 1.0 1.0 Silica 7.8 7.8 7.8Sensory Evaluation Sensation Score (After 10 min.) 3.7 2.9 4.6 SensationDuration (minutes) 46.0 37.0 78.7

Example IV Coolant Activity of Neoisomers

The neo-coolants synthesized according to the routes outlined hereinwere tested to rate their cooling power compared with the correspondingl-isomers (commercially available samples) using the following protocol.Control and test coolants were formulated into a dentifrice at variouslevels according to the following formula.

Dentifrice Formulation With Coolant Level Silica, Dental Type, NF(Zeodent 119)  5.00% Titanium Dioxide for Dentifrice USP  0.53%Carboxymethylcellulose Sodium, USP (7M8SF)  0.75% Tribasic SodiumPhosphate Dodecahydrate  1.10% Sorbitol Solution, USP (LRS) 60.88%Carbomer 956  0.30% Sodium Phosphate Monobasic Monohydrate, USP  0.42%Silica, Dental Type NF Zeodent 119 10.00% Sodium Lauryl Sulfate 28%Solution  4.00% Spearmint Flavor  1.00% Coolant variable Purified Water,USP QS

Panelists (n=9) were instructed to brush for 30 seconds with a controldentifrice (containing a mixture of coolants 1500 ppm l-WS-3, 3000 ppmMenthol, 3000 ppm MGA and 1000 ppm WS-23), expectorate, and assign thecontrol dentifrice a cooling rating of 60 on a 1-90 scale. The panelistswere then given the test dentifrices in random order and instructed tobrush and rate each sample relative to the control over a 60-minuteperiod. Cooling ratings relative to control are summarized below.

Cooling Rating Relative to Control Coolants 0 min 15 min 30 min 45 min60 min 1500 ppm l-WS-3 53.5 36.5 27.0 20.5 15.5 1500 ppm Neo-WS-3 43.333.9 23.3 16.7 13.3  750 ppm Neo-WS-3 + 750 ppm l-WS-3 51.5 33.0 21.514.0  9.0 1500 ppm l-WS-5 53.9 40.0 26.7 17.8 13.3 1500 ppm NeoWS-5 61.939.3 29.3 21.4 15.7  750 ppm Neo-WS-5 + 750 ppm l-WS-5 57.0 44.0 29.021.5 14.0  500 ppm l-Menthyl lactate (2S) 50.0 38.0 26.5 18.5 13.5  500ppm Neo-Menthyl lactate (2S) 62.2 43.9 33.9 27.5 16.7 1950 ppmNeo-Menthyl lactate (~2:1 S:R) 50.6 42.8 30.6 22.2 16.7 1000 ppmNeo-Menthyl pyruvate 57.8 45.0 30.6 21.1 16.1  335 ppm Neo-Menthyllactate acetate (2S) 64.4 46.3 33.1 26.3 21.3

The neoisomers of WS-5 and menthyl lactate showed higher cooling potencyover the l-isomers. Where the neoisomer did not show higher coolingpotency such as with WS-3, blending of the two isomers may still beadvantageous in providing a better in-use experience, such as wasdemonstrated with the G-180 and neo-G-180 blend, wherein the negativesensory effects from using G-180 alone was modulated by the neoisomer.This is believed to result from having two different binding patterns atthe same coolant receptor site. The neo-derivatives of menthyl lactateshowed surprising cooling power. In particular, neo-menthyl lactate (2S)and neo-menthyl lactate acetate[(1S,2S,5R)-2-isopropyl-5-methylcyclohexyl-2(S)-acetoxypropanoate]provided very strong initial cooling as well as over the 60 minute timeperiod, compared to 1-menthyl lactate. The other menthyl lactatederivatives exhibited a similar trend.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm”

All documents cited in the Detailed Description of the Invention are, inrelevant part, incorporated herein by reference; the citation of anydocument is not to be construed as an admission that it is prior artwith respect to the present invention. To the extent that any meaning ordefinition of a term in this written document conflicts with any meaningor definition of the term in a document incorporated by reference, themeaning or definition assigned to the term in this written documentshall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A process for preparing specific isomers ofmenthane derivatives comprising (a) derivatizing a starting menthanealcohol to a sulfonate ester or other leaving group, (b) reacting amenthane alcohol derivative from step (a) with sodium cyanide to obtaina menthane nitrile having opposite stereochemistry at the C-1 positionfrom the starting menthane alcohol and (c) derivatizing the menthanenitrile obtained in step (b) by (i) subjecting the menthane nitrile tohydrolysis conditions comprising hydrogen peroxide and dimethylsulfoxide to obtain a menthane carboxamide having the samestereochemistry as the nitrile, or (ii) subjecting the menthane nitrileto hydrolysis conditions comprising hydrogen bromide to obtain amenthane carboxylic acid having the same stereochemistry as the nitrile,or (iii) subjecting a (1S,2S,5R)-menthane nitrile to hydrolysisconditions comprising potassium hydroxide to obtain a(1R,2S,5R)-menthane carboxylic acid.
 2. The process of claim 1 whereinl-menthol having 1R,2S,5R configuration is used as the starting menthanealcohol to obtain neoiosmers having 1S,2S,5R configuration, of menthanenitrile, menthane carboxylic acid and menthane carboxamide.
 3. A processfor preparing neo-menthane-based derivatives having coolant propertiescomprising derivatizing a neo-menthane carboxylic acid, a neo-menthaneacid chloride or a neo-menthane carboxamide.
 4. A process according toclaim 3, comprising a reaction between an amino compound and aneo-menthane carboxylic acid or a neo-menthane acid chloride to prepareN-substituted-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamidecompounds having coolant properties of general formula

wherein R is selected from linear or branched C1-C8 alkyl, substitutedC1-C8 alkyl and substituted or unsubstituted aryl or heteroaryl.
 5. Aprocess according to claim 4, wherein the amino compound is selectedfrom ethyl amine, tert-butyl amine or glycine ethyl ester to prepareN-ethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide,N-tert-butyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide andN-ethoxycarbonylmethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide,respectively.
 6. A process according to claim 3, comprising a reactionbetween an alkyl halide and neo-menthane carboxamide to prepareN-alkyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide compoundshaving coolant properties.
 7. A process according to claim 6 wherein thealkyl halide is ethyl iodide to prepareN-ethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide.
 8. Aprocess according to claim 3 comprising a reaction between an alcoholand a neo-menthane carboxylic acid or a neo-menthane acid chloride toprepare a neo-menthane carboxy ester.
 9. A process according to claim 8wherein the alcohol is 1,2-ethanediol or 1,2,3-propanetriol to prepare(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylic acid 2-hydroxyethylester (neo-WS-4) and(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylic acid2,3-dihydroxypropyl ester (neo-WS-30) respectively.
 10. A process forpreparing intermediates useful for preparation of neo-menthylderivatives having 1S,2S,5R configuration comprising subjectingneo-menthyl acetate to hydrolysis conditions comprising a base to obtainneo-menthol, wherein neo-menthyl acetate is prepared from l-mentholhaving 1R,2S,5R configuration by (a) reacting l-menthol with tosylchloride to obtain menthyl tosylate which is then reacted with sodiumacetate, or (b) reacting l-menthol in a medium comprising acetic acid,triphenylphosphine (Ph₃P) and diethyl azodicarboxylate(EtO₂C—N═N—CO₂Et).
 11. A process for preparing neo-menthyl derivativeshaving 1S,2S,5R configuration comprising derivatizing neo-menthol.
 12. Aprocess according to claim 11 comprising a reaction between neo-mentholand a derivatizing agent selected from a carboxylic acid, carboxylicacid anhydride, dicarboxylic acid anhydride or carboxylic acid chlorideto obtain a neo-menthyl ester having coolant properties.
 13. A processaccording to claim 12, wherein the derivatizing agent comprises one or amixture of lactic acid, pyruvic acid, succinic acid, 2-acetoxy-propanoicacid chloride, and succinic acid anhydride.
 14. A product forapplication to the mouth, throat or skin comprising an amount of aneo-menthane derivative selected from a neo-menthyl ester, neo-menthylether, neo-menthane carboxy ester or neo-menthane carboxamide, effectiveto give a cooling sensation to the mouth, throat or skin.
 15. A productaccording to claim 14 comprising a blend of a neo-menthyl ester,neo-menthyl ether, neo-menthane carboxy ester or neo-menthanecarboxamide compound with a corresponding l-isomer in a ratio rangingfrom about 1:99 to about 99:1.
 16. A product according to claim 14selected from compositions for oral, throat, health and personal care,edible compositions, and flavor or perfume compositions.
 17. A productaccording to claim 16 in a form selected from mouthwash, gargle,dentifrice, toothpaste, dental tablet, dental powder, dental solution,chewing gum, dental floss or tape, toothpick, throat lozenge, coughsyrup, antacid tablet and digestion aid.
 18. A method of providing acooling effect to the mouth, throat or skin by applying thereto aproduct comprising a neo-menthyl ester, neo-menthyl ether, neo-menthanecarboxamide or neo-menthane carboxy ester compound.